Synaptic Potentiation in Hippocampus by eEF2K Inhibitor A484954

An important mechanism controlling protein synthesis is through phosphorylation of the eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K. Hyperphosphorylation of eEF2 is linked to many neuronal diseases characterized by cognitive impairments. Consistently, recent studies show that the inhibition of the eEF2K signaling via genetic or pharmacological approaches can alleviate synaptic failure and dementia syndromes in mouse models of Alzheimer's disease (AD) and related dementias (ADRDs). One commonly used tool to study eEF2K signaling is A-484954 (or AG), a small molecule compound that is considered a highly selective and potent eEF2K antagonist. Here we reported that the AG compound (at three doses) can induce chemical long-term potentiation (LTP) in acute hippocampal slices from mice. Taking advantage of two transgenic mouse models with eEF2K knockout or overexpression, we further demonstrated that eEF2K-independent mechanisms contribute to chemical LTP induced by AG (dose-dependent). Our data suggest cautious interpretation of findings on neuronal effects of eEF2K inhibitors such as AG. Future investigations are warranted to elucidate the detailed molecular mechanisms underlying the effects of AG compound and other eEF2K inhibitors on synaptic and cognitive function.